The development of pulmonary hypertension in diseases associated with alveolar hypoxia or lung injury is mediated by two mechanisms: pulmonary vascular remodeling and vasoconstriction. The structural changes include medial smooth muscle cell (SMC) hypertrophy and differentiation of precursor cells into SMC. The mechanisms responsible for vasoconstriction may be due to an accelerated vasospastic response of SMC to a stimulus. There is an intimate anatomic association between pulmonary endothelial cells (EC) and vascular SMC in the lung. Based on known interactions between systemic aortic EC and SMC and data we have obtained in pulmonary EC and SMC, we propose that pulmonary EC-derived factor(s) may modify SMC growth and function. The overall objective is to identify the specific cellular biochemical processes involved in the interaction of pulmonary EC (after hypoxia or injury) and vascular SMC. The specific aims are: 1. Determine conditions of pulmonary EC hypoxia or injury which cause release of vascular SMC mitogen(s) including: the time course of release and level of hypoxia; the possibility that hypoxia can injure pulmonary EC; and determination if the EC release of SMC mitogen(s) is a general mechanism or specific for hypoxia. 2. Purify and characterize the SMC mitogen(s) released by EC after hypoxia or injury including: comparison to other EC-derived growth factors; assessment of the effect of each mitogen on SMC division; determining the specificity of the mitogen(s); and studying the interaction of the mitogen(s) with other growth factors. 3. Explore mechanisms of action of EC-derived mitogen(s) in causing SMC proliferation including: SMC arachidonate metabolism; SMC Na+/H+ exchange and its consequences; and secretion of a somatomedin-C like peptide by SMC. 4. Explore possible modulating influence of pulmonary SMC on pulmonary EC mitogen release using co-cultivation system.